Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir.
Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir.
复制标题
肺基质失调通过增强驻留淋巴细胞抑制上皮干细胞库而导致肺气肿恶化。
DOI：
10.1016/j.immuni.2023.01.032
复制
发表时间：
2023
期刊：
影响因子：
32.4
通讯作者：
Peng,Tien
中科院分区：
文献类型：
--
作者：
Wang,Chaoqun;Hyams,Ben;Allen,NancyC;Cautivo,Kelly;Monahan,Kiara;Zhou,Minqi;Dahlgren,MadeleneW;Lizama,CarlosO;Matthay,Michael;Wolters,Paul;Molofsky,AriB;Peng,Tien
Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expressesHhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion ofHhipinduced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.
